Transcription regulatory codes of eukaryotic genomes

Merkulova, T. I.; Ananko, E. A.; Ignatieva, E. V.; Колчанов, Н. А.

doi:10.1134/s1022795413010079

Cited by 9 publications

(5 citation statements)

References 130 publications

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“…Promoters contain specific DNA sequences (transcription factor binding sites), short regions of DNA (10-20 nucleotides) recognized by regulatory proteins (transcription factors). Specific interaction of transcription factors with DNA sequences within promoter region (alone or with other proteins in a complex) facilitates the recruitment of RNA polymerase to specific genes (Merkulova et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

Genetic basis of olfactory cognition: extremely high level of DNA sequence polymorphism in promoter regions of the human olfactory receptor genes revealed using the 1000 Genomes Project dataset

et al. 2014

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The molecular mechanism of olfactory cognition is very complicated. Olfactory cognition is initiated by olfactory receptor proteins (odorant receptors), which are activated by olfactory stimuli (ligands). Olfactory receptors are the initial player in the signal transduction cascade producing a nerve impulse, which is transmitted to the brain. The sensitivity to a particular ligand depends on the expression level of multiple proteins involved in the process of olfactory cognition: olfactory receptor proteins, proteins that participate in signal transduction cascade, etc. The expression level of each gene is controlled by its regulatory regions, and especially, by the promoter [a region of DNA about 100–1000 base pairs long located upstream of the transcription start site (TSS)]. We analyzed single nucleotide polymorphisms using human whole-genome data from the 1000 Genomes Project and revealed an extremely high level of single nucleotide polymorphisms in promoter regions of olfactory receptor genes and HLA genes. We hypothesized that the high level of polymorphisms in olfactory receptor promoters was responsible for the diversity in regulatory mechanisms controlling the expression levels of olfactory receptor proteins. Such diversity of regulatory mechanisms may cause the great variability of olfactory cognition of numerous environmental olfactory stimuli perceived by human beings (air pollutants, human body odors, odors in culinary etc.). In turn, this variability may provide a wide range of emotional and behavioral reactions related to the vast variety of olfactory stimuli.

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Section: Introductionmentioning

confidence: 99%

Genetic basis of olfactory cognition: extremely high level of DNA sequence polymorphism in promoter regions of the human olfactory receptor genes revealed using the 1000 Genomes Project dataset

et al. 2014

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“…Programs -of coordinated switching on, switching off, and changes of the expression of various genes -that underlie (1) ontogenesis events, (2) the existence of many types of differentiated cells, and (3) the abilities of cells to respond to various factors of the external and internal environment are implemented by the regulatory part of the genome of multicel lular organisms. The information encoded in the regulatory regions is converted into a desired pattern of gene expression primarily via the binding of TFs to specific sequences in the regulatory regions (e. g., promoters, enhancers, and silencers) (Lan et al, 2012;Merkulova et al, 2013;DuboisChevalier et al, 2018;Chen, Pugh, 2021;Tobias et al, 2021). Accord ing to presentday concepts, the SNPs located in regulatory regions of genes, affecting binding sites of TFs, and changing the level of gene expression play a central part in the varia tion of phenotypic traits, including predisposition/resistance to multifactorial diseases (Maurano et al, 2015;Deplancke et al, 2016;Carrasco Pro et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Human-genome single nucleotide polymorphisms affecting transcription factor binding and their role in pathogenesis

Antontseva,

Degtyareva,

Korbolina

et al. 2023

Vestn. VOGiS

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Single nucleotide polymorphisms (SNPs) are the most common type of variation in the human genome. The vast majority of SNPs identified in the human genome do not have any effect on the phenotype; however, some can lead to changes in the function of a gene or the level of its expression. Most SNPs associated with certain traits or pathologies are mapped to regulatory regions of the genome and affect gene expression by changing transcription factor binding sites. In recent decades, substantial effort has been invested in searching for such regulatory SNPs (rSNPs) and understanding the mechanisms by which they lead to phenotypic differences, primarily to individual differences in susceptibility to di seases and in sensitivity to drugs. The development of the NGS (next-generation sequencing) technology has contributed not only to the identification of a huge number of SNPs and to the search for their association (genome-wide association studies, GWASs) with certain diseases or phenotypic manifestations, but also to the development of more productive approaches to their functional annotation. It should be noted that the presence of an association does not allow one to identify a functional, truly disease-associated DNA sequence variant among multiple marker SNPs that are detected due to linkage disequilibrium. Moreover, determination of associations of genetic variants with a disease does not provide information about the functionality of these variants, which is necessary to elucidate the molecular mechanisms of the development of pathology and to design effective methods for its treatment and prevention. In this regard, the functional analysis of SNPs annotated in the GWAS catalog, both at the genome-wide level and at the level of individual SNPs, became especially relevant in recent years. A genome-wide search for potential rSNPs is possible without any prior knowledge of their association with a trait. Thus, mapping expression quantitative trait loci (eQTLs) makes it possible to identify an SNP for which – among transcriptomes of homozygotes and heterozygotes for its various alleles – there are differences in the expression level of certain genes, which can be located at various distances from the SNP. To predict rSNPs, approaches based on searches for allele-specific events in RNA-seq, ChIP-seq, DNase-seq, ATAC-seq, MPRA, and other data are also used. Nonetheless, for a more complete functional annotation of such rSNPs, it is necessary to establish their association with a trait, in particular, with a predisposition to a certain pathology or sensitivity to drugs. Thus, approaches to finding SNPs important for the development of a trait can be categorized into two groups: (1) starting from data on an association of SNPs with a certain trait, (2) starting from the determination of allele-specific changes at the molecular level (in a transcriptome or regulome). Only comprehensive use of strategically different approaches can considerably enrich our knowledge about the role of genetic determinants in the molecular mechanisms of trait formation, including predisposition to multifactorial diseases.

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“…The computer methods for recognition of TFBSs in DNA sequences are free of this disadvantage but yet ineffective in detection of both TFBSs and the SNPs changing these sites without the cooperation with omics experiments. The objective reasons here are a high degeneracy of the regulatory DNA code [15,109,181,182]; high importance of low-affinity sites in gene regulation [183]; the presence of structural variants of the binding sites for the same TF [184][185][186][187]; and even nonconsensus TFBSs [188,189]. All these facts considerably decrease the efficacy of the available methods for TFBS recognition, most of which are based on the PWM model, which oversimplifies the mechanisms underlying TF-DNA interaction [66,[68][69][70].…”

Section: Discussionmentioning

confidence: 99%

“…There, the interplay between these TFs and their binding sites (cis-regulatory elements) as well as the interaction of TFs with one another and the coactivator and chromatin remodeling complexes orchestrate the dynamic and diverse genetic programs, thereby determining the tissue-specific gene expression, spatiotemporal specificity of gene activities during development, and the ability of genes to respond to different external signals [7][8][9][10][11][12]. Thus, thanks to the binding to their specific sites on DNA (transcription factor binding sites, TFBSs), TFs directly interpret the regulatory part of the genome, performing the first step in deciphering the DNA sequence [13][14][15]. Consequently, regulatory SNPs (rSNPs), that is, genetic variation within TFBSs that alters expression, play a central role in the phenotypic variation in complex traits, including the risk of developing a disease.…”

Section: Introductionmentioning

confidence: 99%

Regulatory SNPs: Altered Transcription Factor Binding Sites Implicated in Complex Traits and Diseases

Degtyareva

Antontseva

Merkulova

2021

IJMS

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The vast majority of the genetic variants (mainly SNPs) associated with various human traits and diseases map to a noncoding part of the genome and are enriched in its regulatory compartment, suggesting that many causal variants may affect gene expression. The leading mechanism of action of these SNPs consists in the alterations in the transcription factor binding via creation or disruption of transcription factor binding sites (TFBSs) or some change in the affinity of these regulatory proteins to their cognate sites. In this review, we first focus on the history of the discovery of regulatory SNPs (rSNPs) and systematized description of the existing methodical approaches to their study. Then, we brief the recent comprehensive examples of rSNPs studied from the discovery of the changes in the TFBS sequence as a result of a nucleotide substitution to identification of its effect on the target gene expression and, eventually, to phenotype. We also describe state-of-the-art genome-wide approaches to identification of regulatory variants, including both making molecular sense of genome-wide association studies (GWAS) and the alternative approaches the primary goal of which is to determine the functionality of genetic variants. Among these approaches, special attention is paid to expression quantitative trait loci (eQTLs) analysis and the search for allele-specific events in RNA-seq (ASE events) as well as in ChIP-seq, DNase-seq, and ATAC-seq (ASB events) data.

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Transcription regulatory codes of eukaryotic genomes

Cited by 9 publications

References 130 publications

Genetic basis of olfactory cognition: extremely high level of DNA sequence polymorphism in promoter regions of the human olfactory receptor genes revealed using the 1000 Genomes Project dataset

Genetic basis of olfactory cognition: extremely high level of DNA sequence polymorphism in promoter regions of the human olfactory receptor genes revealed using the 1000 Genomes Project dataset

Human-genome single nucleotide polymorphisms affecting transcription factor binding and their role in pathogenesis

Regulatory SNPs: Altered Transcription Factor Binding Sites Implicated in Complex Traits and Diseases

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